Principles of Molecular Virology

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Monday, 2 March 2015

Principles of Molecular Virology, Chapter 6 (Virus Infection), discusses virus infections of plants and animals, and examines the similarities and the differences between them.

I've been updating my lecture notes for students and writing self-assessment questions for the Principles of Molecular Virology website, and in the course of my research I came across the following useful articles about virus infection of plants - and how plants fight infection. All these are freely available via Open Access (search for the title of each paper on Google Scholar).

The first paper considers how virus infections of plants cause disease, although this is not an inevitable outcome of infection. As in animals, plant antiviral systems often contribute to symptoms of infection:

Pallas, V., & García, J. A. (2011) How do plant viruses induce disease? Interactions and interference with host components. Journal of General Virology, 92(12), 2691-2705 Abstract:
Plant viruses are biotrophic pathogens that need living tissue for their multiplication and thus, in the infection–defence equilibrium, they do not normally cause plant death. In some instances virus infection may have no apparent pathological effect or may even provide a selective advantage to the host, but in many cases it causes the symptomatic phenotypes of disease. These pathological phenotypes are the result of interference and/or competition for a substantial amount of host resources, which can disrupt host physiology to cause disease. This interference/competition affects a number of genes, which seems to be greater the more severe the symptoms that they cause. Induced or repressed genes belong to a broad range of cellular processes, such as hormonal regulation, cell cycle control and endogenous transport of macromolecules, among others. In addition, recent evidence indicates the existence of interplay between plant development and antiviral defence processes, and that interference among the common points of their signalling pathways can trigger pathological manifestations. This review provides an update on the latest advances in understanding how viruses affect substantial cellular processes, and how plant antiviral defences contribute to pathological phenotypes.

This paper discusses plant disease resistance (R) genes, the equivalent to the immune system in animals:

Finally, this article takes a wider look at anti-viral mechanisms in plants, and discusse how innate immunity and RNA silencing act together to defend plants against viruses and other pathogens:

Zvereva, A.S., & Pooggin, M.M. (2012) Silencing and innate immunity in plant defense against viral and non-viral pathogens. Viruses, 4(11), 2578-2597 Abstract:
The frontline of plant defense against non-viral pathogens such as bacteria, fungi and oomycetes is provided by transmembrane pattern recognition receptors that detect conserved pathogen-associated molecular patterns (PAMPs), leading to pattern-triggered immunity (PTI). To counteract this innate defense, pathogens deploy effector proteins with a primary function to suppress PTI. In specific cases, plants have evolved intracellular resistance (R) proteins detecting isolate-specific pathogen effectors, leading to effector-triggered immunity (ETI), an amplified version of PTI, often associated with hypersensitive response (HR) and programmed cell death (PCD). In the case of plant viruses, no conserved PAMP was identified so far and the primary plant defense is thought to be based mainly on RNA silencing, an evolutionary conserved, sequence-specific mechanism that regulates gene expression and chromatin states and represses invasive nucleic acids such as transposons. Endogenous silencing pathways generate 21-24 nt small (s)RNAs, miRNAs and short interfering (si)RNAs, that repress genes post-transcriptionally and/or transcriptionally. Four distinct Dicer-like (DCL) proteins, which normally produce endogenous miRNAs and siRNAs, all contribute to the biogenesis of viral siRNAs in infected plants. Growing evidence indicates that RNA silencing also contributes to plant defense against non-viral pathogens. Conversely, PTI-based innate responses may contribute to antiviral defense. Intracellular R proteins of the same NB-LRR family are able to recognize both non-viral effectors and avirulence (Avr) proteins of RNA viruses, and, as a result, trigger HR and PCD in virus-resistant hosts. In some cases, viral Avr proteins also function as silencing suppressors. We hypothesize that RNA silencing and innate immunity (PTI and ETI) function in concert to fight plant viruses. Viruses counteract this dual defense by effectors that suppress both PTI-/ETI-based innate responses and RNA silencing to establish successful infection.

Friday, 16 January 2015

Wednesday, 10 December 2014

A few days ago the postman brought me a parcel - the new Korean edition of Principles of Molecular Virology. Unfortunately, I can't read Korean, but this is still very exciting. I think this is the fifth language Principles of Molecular Virology has been translated into, but to be honest, I've lost count.

But here is even more exciting news! Yesterday I delivered the finished version of the new 6th edition of Principles of Molecular Virology to the publisher! This had been long delayed - the manuscript was due in September - but it's now full steam ahead and the new edition will be out early in next year.

I'll be sharing sections of the new edition with you here over the next few months, but here's a taster - the Preface, which explains why I wrote this book:

Preface to the Sixth Edition

In the age of the Internet, why would anyone write a textbook about virology? Indeed, why would anyone write anything about virology? Virology isn't dead yet (DiMaio, 2014), and neither are books. I encourage everyone to use the wonderful resource of the Internet to improve their knowledge of virology. I encourage my students to use Wikipedia and Google to learn the facts. But as Jimmy Wales said, Wikipedia is often the best place to start, but the worst place to stop. The role of this book is not primarily about knowledge but about sense-making - what you can't get from Wikipedia. Virology explained by setting facts in a larger context. Along with updating the facts and smoothing some of the rough edges, I have noticed a big scientific change in writing this edition. Open Access scientific publishing has finally made its impact felt. In updated the reading recommendations at the end of each chapter I have been able, in almost all cases, to recommend freely available peer-reviewed content for readers. You may have to hunt around to find it – a good working knowledge of PubMed and Google Scholar is at least as useful as Google and Wikipedia – but it is now possible to access much of the scientific literature the public has paid for. But there is still the question of interpretation. In writing this book I have tried to do my part. The rest is up to the reader.As with previous editions, I am grateful to the staff of Elsevier, in particular Halima Williams and Jill Leonard, for their patience with me. DiMaio, D. (2014). Is Virology Dead? mBio, 5(2), e01003-14.Alan J. CannUniversity of Leicester, UKDecember 2014

Wednesday, 19 November 2014

Principles of Molecular Virology, Chapter 6 (Virus Infection), discusses not only the treatment of virus infections, but also how viruses can be used to treat infections.

Phage therapy, the use of bacteriophages to treat or prevent disease, stretches back nearly a century to the earliest days of the discovery of phages. Long before the discovery of antibiotics, the thought that viruses which lyse bacteria could be used to treat diseases was highly attractive. Soon after the discovery of bacteriophages by Frederick Twort (1915) and Felix d'Hérelle (1917), treatment of bacterial infections in humans was tried. This reference gives a good overview of the advantages and the disadvantages of this approach.

Loc-Carrillo C., and Abedon S.T. (2011) Pros and cons of phage therapy. Bacteriophage 1(2): 111–114. doi: 10.4161/bact.1.2.14590Many publications list advantages and disadvantages associated with phage therapy, which is the use of bacterial viruses to combat populations of nuisance or pathogenic bacteria. The goal of this commentary is to discuss many of those issues in a single location. In terms of "Pros," for example, phages can be bactericidal, can increase in number over the course of treatment, tend to only minimally disrupt normal flora, are equally effective against antibiotic-sensitive and antibiotic-resistant bacteria, often are easily discovered, seem to be capable of disrupting bacterial biofilms, and can have low inherent toxicities. In addition to these assets, we consider aspects of phage therapy that can contribute to its safety, economics, or convenience, but in ways that are perhaps less essential to the phage potential to combat bacteria. For example, autonomous phage transfer between animals during veterinary application could provide convenience or economic advantages by decreasing the need for repeated phage application, but is not necessarily crucial to therapeutic success. We also consider possible disadvantages to phage use as antibacterial agents. These "cons," however, tend to be relatively minor.

Yet after the initial enthusiasm, this idea has never become a widespread practical reality. Devotees of phage therapy defend their cherished belief with almost religious fervor, but there are serious obstacles to be overcome, such as the narrow host range of most phages (a few strains of bacteria, not even an entire species) and the speed at which bacteria develop resistance to infection. An entertaining account is given by William Summers:

"The history of phage therapy, since the discovery of phages a century ago, has been fraught with conflicting observations, misinterpretations, and incomplete understanding, all of which are part of normal science. But there is more: the history of phage therapy is rich with politics, personal feuds, and unrecognized conflicts. Understanding these extra-scientific aspects of its history can help explain the tortuous course of phage therapy over the past century."Summers, W.C. The strange history of phage therapy. (2012) Bacteriophage. 2(2): 130–133. doi: 10.4161/bact.20757

As the spectrum of clinically useful antibiotics dwindles in the face of an ever increasing number of multiple-resistant "superbugs", phage therapy increases in attractiveness, but is unlikely ever to replace the antibiotic golden era of disease treatment we are now leaving behind. There are some particular areas where the concept is especially interesting - tackling biofilms for example. Bacteria embedded in the matrix of a biofilm are often more resistant to antibiotic treatment than free "planktonic" baceria. As the significance of biofilms increases with the rise of medical devices, this is an area where phage therapy is worth investigating.

Tuesday, 29 April 2014

Principles of Molecular Virology points out that size alone does not distinguish viruses from other microbes such as bacteria. And new virus discoveries just keep getting more diverse.

It's a common mistake that "viruses are smaller than bacteria". While that's true in most cases, it's not always so. The largest viruses have longer genomes and bigger particles than the smallest bacterial cells, so size alone does not distinguish them. These viruses are large enough to be visible under a good light microscope. At first, Mimivirus ruled the roost as the largest known virus. Then along came the Megaviridae which were slightly bigger. Recently, another group of giant viruses have been discovered - the Pandoraviruses. Earlier this year, another type of giant virus, Pithovirus sibericum, was isolated from the Siberian permafrost using Acanthamoeba as bait, causing some discussion that revival of such viruses due to thawing of permafrost either from global warming or industrial exploitation of circumpolar regions might cause future threats to human or animal health (Nature News & Comment: Infectious diseases: Smallpox watch).

All these giant viruses have double stranded DNA genomes over a million base pairs long, nearly 3 Mbp in the case of some of the Pandoraviruses. But their particles are distinct in shape, Mimivirus particles having icosahedral capsids of about 0.5 µm in diameter, while Pandoraviruses have "amphora-shaped" particles from 1–1.2 μm in length.

So what are we to make of all these giant viruses (the "nucleocytoplasmic large DNA viruses" as they are now being called)? Clearly they are not so unusual as we thought 10 years ago when Mimivirus was isolated, and recent discoveries show they are much more diverse than we initially assumed. And they proved we still have a lot to find out about virology.

Pandoraviruses: Amoeba viruses with genomes up to 2.5 Mb reaching that of parasitic eukaryotes. (2013) Science 341(6143): 281–286
Ten years ago, the discovery of Mimivirus, a virus infecting Acanthamoeba, initiated a reappraisal of the upper limits of the viral world, both in terms of particle size (>0.7 micrometers) and genome complexity (>1000 genes), dimensions typical of parasitic bacteria. The diversity of these giant viruses (the Megaviridae) was assessed by sampling a variety of aquatic environments and their associated sediments worldwide. We report the isolation of two giant viruses, one off the coast of central Chile, the other from a freshwater pond near Melbourne (Australia), without morphological or genomic resemblance to any previously defined virus families. Their micrometer-sized ovoid particles contain DNA genomes of at least 2.5 and 1.9 megabases, respectively. These viruses are the first members of the proposed “Pandoravirus” genus, a term reflecting their lack of similarity with previously described microorganisms and the surprises expected from their future study.

Thirty-thousand-year-old distant relative of giant icosahedral DNA viruses with a pandoravirus morphology. (2014) Proceedings of the National Academy of Sciences, 111(11), 4274-4279
Giant DNA viruses are visible under a light microscope and their genomes encode more proteins than some bacteria or intracellular parasitic eukaryotes. There are two very distinct types and infect unicellular protists such as Acanthamoeba. On one hand, Megaviridae possess large pseudoicosahedral capsids enclosing a megabase-sized adenine–thymine-rich genome, and on the other, the recently discovered Pandoraviruses exhibit micron-sized amphora-shaped particles and guanine–cytosine-rich genomes of up to 2.8 Mb. While initiating a survey of the Siberian permafrost, we isolated a third type of giant virus combining the Pandoravirus morphology with a gene content more similar to that of icosahedral DNA viruses. This suggests that pandoravirus-like particles may correspond to an unexplored diversity of unconventional DNA virus families.